Designing Control Rooms For Reliable Operation

Modern process control equipment requires stringent protection from pulp and paper mill
environments in order to maintain reliability and maximum useful equipment life. State of the
art installations will typically require an operator control room and a process computer room.
The operator control room will contain CRT-based consoles, printers, video copiers, annunciator
panels, recorders and possible backup panels. Backup panels are at the point of being eliminated
in some current installations with the growth of confidence in digital control systems and ability
to build in redundancy.
All equipment required for operator interface with the process is contained in the operator
control room. The process computer room will contain input/output devices, microprocessorbased
control devices, multiplexers, computers and mass storage devices. These will usually be
separate but contiguous to the operator control room.
Both the operator control room and computer room require appropriate design and
construction features to protect the equipment against environmental and process hazards.
Electrical control rooms which contain controls for electrically driven equipment should
be constructed in a similar manner. Depending on the equipment to be housed in the room and
ambient air conditions, air purification requirements similar to those for operator control rooms
and computer rooms are required.
Recommendations
Access to computer rooms and operator control rooms must be regulated. Only people
with a legitimate need to be there should be permitted in these rooms. These rooms should be
marked clearly as “Restricted” or “Authorized Personnel Only.”
All doorways used regularly by personnel must be provided with air locks to prevent
infiltration of contaminants.
Computer and operator control rooms should be located and constructed in such a manner
that equipment is protected from exposure to operating hazards, excessive ambient air conditions
and excessive vibration. Close access to the process is often of secondary importance to the
security of control equipment and comfort.
Operator control rooms should have a noise level below 60 decibels. Construction
materials are available to achieve this level.
Fluorescent lighting is preferred because it generates less heat than incandescent fixtures
and illuminates the work area more evenly. Light fixtures that minimize glare should be used to
reduce the problem of operator fatigue. Also, it is important to prevent the light source from
being reflected from the surfaces of control displays into the operator’s eyes.
Sectional lighting control can be used to appropriately zone the individual lighting
requirements within the control room. To further reduce eye strain and fatigue, lighting level
controls are an effective means of allowing the operator to adjust the lighting level.
Critical control rooms should be supplied from more than one lighting circuit-breaker to
reduce the possibility of a blackout. Emergency lighting for passageways and panel illumination
for continued operation should always be provided.
Operator control rooms usually require raised floors under which wiring and cables are
run for interconnection of the electronic equipment. All conduit and cable entries into operator
control rooms should be routed below the raised floor. This requirement also applies to
computer rooms which have raised floors. Entries should be through the sub-floor or the wall
into the space between the raised floor and the sub-floor.
All conduit and cable entries must be tightly sealed to preserve the integrity of
pressurized rooms. In all sealing methods, the principal concerns are fire rating, moisture,
chemical resistance and the effectiveness of seals. Fire-resistant foam sealant is one of the
preferred sealing methods. The sealant must surround every cable within a penetration to ensure
the best possible seal.
The complete structure must be designed as a fire-resistant building. Fire protection is
necessary and can be best provided by the installation of a Halon Automatic Fire Protection
System. Air conditioning ducts should be equipped with automatic fire dampers.
Smoke alarms with audible warning systems are recommended. Alarms should sound in
the control rooms and vicinity and also at designated remote stations. Fire detection and alarm
systems are particularly important in process computer rooms which are not normally occupied.
Air conditioning systems selected for operator control rooms and computer rooms should
be installed so that there is no possibility of water entering the operator control room or computer
room. Since total loss of air conditioning must be avoided, two half-size units are recommended
as a minimum requirement. Window-type air conditioning units are not recommended.
Temperature and humidity should be controlled within the appropriate limits in order to
minimize corrosion, condensation, prevent problems from static electricity and provide for
operator comfort. Dry bulb temperature should be contained within a range of 68ºF to 78ºF.
Relative humidity should be controlled within a range of 35 percent to 50 percent. 35
percent RH is a minimum for operator comfort and for minimizing static electricity. 50 percent
RH is a maximum for minimizing corrosion.
Both temperature and relative humidity should be regulated at a reasonably constant
level. +/-3ºF and +/- 5 percent RH is suggested.
A pressurizing air system supplying purified air which can sustain 0.08-inch H2O
pressure inside the control/computer rooms is recommended. This system should be capable of
supplying two volume changes per hour for well-sealed rooms. Tightly sealed rooms are of
paramount importance to avoid excessive air changes and the intrusion of corrosive gases.
A deep-bed activated carbon filter system is recommended to remove corrosive
contaminants from the makeup pressurization air supply. The complete system should consist of
particulate filtering elements, blower, ducting, and a deep bed of activated carbon capable of
removing significant amounts of hydrogen sulfide, sulfur dioxide, and chlorine gases.
Concentrations of all corrosive gases in the makeup air should be reduced as much as possible,
preferably below a target of 5 ppb. The carbon bed should have a service life in excess of one
year, although the actual service life will depend on ambient concentrations of contaminant gases
which are adsorbed.
A room static differential pressure detector and low differential pressure alarm are
desirable to indicate loss of adequate room pressure. The alarm would have a time-delay feature
to prevent accidental triggering if both air-lock doors are open simultaneously for a short time
period.
Operator control rooms and computer rooms must be carefully constructed. No holes or
openings should be left in any room surfaces where contaminants, rain or leaks of any liquid can
enter the room. When electronic equipment is present in the room before construction is
completed, all entrances or holes through walls or floors must be shelter-protected and
temporarily sealed.
All openings must be permanently grouted, sealed and flashed before job completion.
All penetrations of pipelines used for water, steam, and process fluids must be avoided. Care
must be taken to minimize the possibility of spills or pipeline failures infiltrating these control
room areas.
To the extent possible, location of overhead piping or equipment which can leak or spray
their contents onto the room should be avoided. Special attention needs to be given to the
sealing of wall to roof deck, wall to ceiling slab, door and window perimeters and air
conditioning ducts or other penetrations through walls and hung ceilings to assure as few
opportunities of air leakage as possible.
A cast-in-place concrete slab is the preferred type of roof construction because it renders
the best watertight and impact-resistant roof.
On top of the concrete roof deck, a built-up roofing system over rigid insulation with a
vapor barrier should be installed. As an alternate to the conventional built-up roofing, an
approved single-ply roofing system may be used.
Ceiling slabs used as a floor should have a cast-in-place concrete slab using shrinkagecompensating
Portland Cement. On top of the structural roof slab, a layer of 0.070-inch thick
membrane waterproofing should be installed to prevent moisture penetration. The membrane
should be topped with a minimum of 3 inches of protective shrinkage-compensating concrete.
The concrete floor which serves as the ceiling should be pitched towards floor drains located
away from control room area.
Walls obviously must be constructed to be air-tight. Masonry walls serve this
requirement well in many instances. Other types of wall construction can be used provided
construction details keep air leakage to a minimum.
The elevation of the finished concrete floor in relation to adjacent floors should be a
minimum of 4 inches to provide protection from possible flooding.
Raised computer floor systems should be a conventional rigid grid support system
provided with suitable pedestal height for access to wiring. Floor finish should be staticinhibiting.
Treatment of concrete sub-floors to prevent dusting is recommended.
A typical construction for ceilings within the operator control area is a suspended T-bar
type with acoustical panels. Sufficient space should be allowed above the suspended ceiling to
install HVAC ducts and lighting fixtures.
The interior of an operator control room should be aesthetically pleasing in terms of color
choices and lighting. The use of appropriate colors can improve operator alertness and minimize
glare. This is a very subjective matter and the advice of a knowledgeable consultant is
recommended.
In summary, the design of process control rooms need not be difficult, just carefully
done. As long as electronic process control equipment is protected from environmental and
process hazards, the control room is at least adequately designed. But to really protect valuable
electronic and analog equipment, a control room designed with the above specifications in mid is
necessary.

Corrosion Prevention in Electrical Control Rooms

Environmental guidelines to eliminate corrosion failures of control equipment were
developed from studies of atmospheric corrosivity in a bleached kraft mill.
The action of extremely small quantities of corrosive gases can cause intermittent or
permanent failures in electrical equipment in pulp and paper mill control rooms (1, 2).
Electronic microcircuits will fail prematurely in corrosive gas concentrations as much as two
orders of magnitude below the maximum concentrations permitted for worker exposure.
Corrosion failures of electrical equipment usually occur by the complete consumption or
breakage of fine wires or by the accumulation of resistive corrosion products between circuit
breaker contacts. Electronic microcircuits most frequently fail at mating connectors where thin
resistive layers of corrosion products spread across the noble metal contact services, or where
condensed electrolytes allow leakage currents to flow between adjacent conductors (2, 3).
Corrosion products have been found to spread across gold-plated connector surfaces at rates of
up to one millimeter in ten hours in parts-per-billion (ppb) concentrations of chlorine and
hydrogen sulfide (4). In one survey of pulp and paper mill control rooms, approximately 80% of
the rooms monitored had environments that would cause premature failures of electronic
microcircuits (1).
Our previous mill studies (5) showed that premature failures of microcircuits only
occurred in environments where the total concentration of corrosive gases (the sum of the
chlorine, hydrogen sulfide, and sulfur dioxide) exceeded 10 ppb. To eliminate premature failures
in electronic equipment, it was recommended that the control room environment should contain
no more than 5 ppb of corrosive gases.
In the present work, relationships between atmospheric corrosivity and control equipment
failure were examine in a study of 86 control rooms in a single bleached kraft mill. Room
environment guidelines have been developed to eliminate premature corrosion failures in
electrical equipment and electronic microcircuits. The proportion of control rooms requiring
environmental upgrading in the mill studied, and the relationship between the corrosivity of a
control room atmosphere and its location in the mill are also discussed.
The Experiment
Monitoring of atmospheric corrosivity
Atmospheric corrosivity was measured with copper metal coupons prepared by
proprietary procedures developed to produce reproducibly reactive surfaces covered by
uniformly thin oxides. Copper was chosen because its corrosion rate is affected by all the major
corrosive gases (chlorine gases and oxidized and reduced sulfur gases). Coupons were
transported to and from the control rooms in heat-sealed multilayer polymer bags, shown by
controlled environment laboratory tests to prevent the intrusion of corrosive gases. Pairs of
coupons were exposed side by side alongside control equipment in the electrical control rooms
for 90-day periods. Briefer exposure periods gave data that could not be reliably extrapolated,
due to the variability of room environments.
After the coupons has been exposed, their corrosion film thicknesses were measured
electrochemically using proprietary cathodic stripping voltammetry procedures. The average
distance between the corrosion film thicknesses on paired coupons was less than +/- 9% of their
average film thickness for films thinner than 0.1 micrometers, and less than +/- 6.5% of their
average film thickness for films thicker than 0.1 micrometers.
To facilitate comparison of the atmospheric corrosivity results with published data
expressed as the corrosion film thickness produced on copper in a year, equivalent annual
corrosion rates were calculated using parabolic kinetics, i.e., the corrosion film was assumed to
thicken in proportion to the square root of the exposure duration.
Monitoring of concentration of corrosive gases
Concentrations of corrosive gases were measured using proprietary cartridges containing
a series of discs impregnated with reagents to chemically bind chlorine, hydrogen sulfide, and
sulfur dioxide (5). Control room air was drawn through the cartridges for one week at a flow of
1 L/min. X-ray fluorescence techniques were developed to measure the concentration of bound
species. Volumetric concentrations of corrosives were calculated using data from cartridge
standards prepared in laboratory exposures to standard concentrations of corrosives.
Results and Discussion
Relationships between atmospheric corrosivity and equipment failure
The atmospheric corrosivity in each of the 86 electrical rooms in the mill was measured
during a 90-day period, using the coupon monitoring procedures described above. Corrosionrelated
failure histories of control equipment in these rooms were obtained from electrical
maintenance staff. Table 1 summarizes the data, showing the minimum atmospheric corrosivity
that caused the different types of failure. Electrical equipment failed in three years in rooms
where the atmospheric corrosivity produced more than 0.5 micrometers of corrosion product in a
year. Almost all of the 86 electrical rooms also contained electronic microcircuits in
programmable logic controllers. Numerous intermittent failures of microcircuits were found in
rooms where the atmospheric corrosivity exceeded 0.17 micrometer of corrosion product per
year. Complete failures of electronic equipment occurred after three to four years’ service in
rooms where the atmospheric corrosivity exceeded 0.19 micrometer of corrosion product per
year, after two years of service where the atmospheric corrosivity exceeded 0.76 micrometer per
year, and after one year of service where atmospheric corrosivities exceeded 1.3 micrometers per
year.
These results indicate that in order to eliminate premature corrosion failures in control
rooms containing electrical equipment only (no electronic equipment), the atmosphere must
produce less than 0.5 micrometer per year of corrosion product on the copper coupons. To
eliminate premature failures of electronic equipment, the control room atmosphere must produce
significantly less than 0.2 micrometer per year of corrosion product on the copper coupons. A
guideline of 0.1 micrometer per year was chosen as a practical maximum corrosivity to
safeguard electronic equipment.
Reduction of atmospheric corrosivity
From these guidelines it was predicted that 28 of the 86 control rooms contained
atmospheres that would cause premature failures of electrical equipment. These 28 and 20 other
rooms contained atmospheres that would be expected to cause premature failures of electronic
equipment. Measures recommended to the mill to upgrade the environments in the unacceptable
rooms included sealing up leakage paths that allowed the ingress of corrosive gases, controlling
the humidity, and chemically filtering the corrosive gases from the control room air. Where
improved sealing and humidity control were inadequate, the mill installed Westvaco Vapor
Adsorber® units. Previous work (6) has shown that control room environments can be
effectively upgraded by purging sealed rooms with air purified by reaction with the deep bed of
specialty activated carbon in these units. Maintaining an overpressure of purified air of more
than 20 Pa (0.08 inch of water) in the control rooms has been found to reduce the intrusion of
corrosive gases to acceptable levels and thereby eliminate premature corrosion failures of the
control equipment.
Concentrations of corrosive gases in selected rooms
In order to estimate the concentration of corrosive gases that would correspond with the
guideline limits for atmospheric corrosivity measured by copper coupons, gas analysis was
performed in selected rooms. The average concentration of chlorine, hydrogen sulfide, and
sulfur dioxide was measured in five of the electrical control rooms during a one-week period
following the coupon monitoring. The data are presented in Table II. The very low
concentrations of these gases (low parts-per-billion levels) illustrates the high reactivity of these
gases with control equipment and the criticality of the chlorine concentration.
The three control rooms in which the coupons formed between 0.14 and 0.24
micrometers per year of corrosion product contained less than 0.5 ppb of chlorine and 3 to 8 ppb
of hydrogen sulfide. The two rooms in which the coupons formed 4.23 and 7.00 micrometers
per year of corrosion product contained 4.2 and 3.4 ppb of chlorine and 9.2 and 1.5 ppb of
hydrogen sulfide. The fact that the room where the corrosive gas concentrations were higher
produced a lower copper coupon corrosion rate probably indicates a variability in the
atmospheric composition during the test periods in a poorly-sealed room. Comparing the data
from the two groups of rooms indicates that increasing the chlorine concentration from 0.5 to 3
or 4 ppb, when the hydrogen sulfide concentration is between 2 and 9 ppb, produces and
environment more than eight times more corrosive than the allowable guidelines for electrical
equipment.
These data are consistent with previous studies from which we have concluded that to
eliminate corrosion failures in electronic equipment, chlorine concentrations should not exceed 1
ppb, hydrogen sulfide concentrations should not exceed 3 ppb, and sulfur dioxide concentrations
should not exceed 3 ppb, and the relative humidity should be maintained below 50%. These
allowable gas concentrations could probably be doubled for rooms containing electrical
equipment only (no microcircuits).
Relationships between room location and atmospheric corrosivity
The predictability of control room atmospheric corrosivity according to room location
was studied by indicating the room locations and corrosivities on a plan of the mill. The rooms
with the most corrosive atmospheres were generally located adjacent to and downwind and
known sources of corrosives, namely the power and recovery boilers and the unbleached and
bleached pulp mills. However, a few rooms with highly corrosive environments were found in
locations expected to be largely free of corrosives, such as the paper mill, and a few rooms were
found to have mild environments in locations close to major sources of corrosives, such as the
bleach plant. It was concluded that factors which cannot be quantified, such as room
construction and local wind direction, preclude the prediction of atmospheric corrosivity based
on mill location. To determine the effect of room environment on control equipment life, it is
necessary to measure the atmospheric corrosivity in the room concerned, using copper coupons.
It should be noted that the presence or absence of odorous gases is not a reliable
indication of atmospheric corrosivity in control rooms. The allowable limits for chlorine,
hydrogen sulfide, and sulfur dioxide mentioned above are far below human olfactory limits. On
the other hand, related laboratory studies, as illustrated in Table III, have shown that even partper-
million concentrations of odorous organic sulfide gases produced in the kraft pulping process
are not corrosive.
Conclusions
The likelihood of corrosion-related failures of control equipment can be determined from
the corrosion rate of specially-prepared coupons exposed for 9-day periods in the environment
concerned. A systematic corrosion study of all the electrical rooms in a bleached kraft mill
indicated that electrical equipment failed when the coupon corrosion rate exceeded the
equivalent of 0.5 micrometer per year, and that electronic equipment failed when the coupon
corrosion rate exceeded the equivalent of about 0.2 micrometer per year. Within the range of
concentrations of corrosive gases found in the selected rooms, the concentration of chlorine was
found to be the most influential factor determining the corrosion rate. Knowing the location of a
control room in relation to known sources of corrosives is insufficient to estimate its atmospheric
corrosivity. Purging of control rooms with highly purified air to maintain a positive room
overpressure reduces the concentration of atmospheric corrosives to levels that eliminate
corrosion failures in control equipment.
Literature Cited
1. Abbott, W. H., 1983 Pulp and Paper Industry Technical Conference Proceedings, IEEE,
New York, p. 39.
2. Noon, D. W., Proceedings of the Third ASM Conference on Electronic Packaging,

Guidelines for Protection of Electronic Equipment in Control Rooms

1. Apply between two and five air changes per hour (ACH) from the Vapor Adsorber
based on the room volume (note – older rooms may require more than 5 ACH).
2. Positively pressurize the room to a level of 0.08 – 0.25 in. w.g.
3. Locate the HVAC system, the Vapor Adsorber and all ductwork within the protected
area where possible. Any components of the system that are located outside of the
protected space must be completely sealed and properly maintained.
4. Locate both the HVAC system and the Vapor Adsorber to minimize the intake of
corrosive gases and to provide accessibility for maintenance.
5. Maintain a room temperature of 68 – 78 oF and a relative humidity of 35 – 50%.
6. Size the HVAC system to offset both the latent and sensible load from the Vapor
Adsorber makeup air.
7. Ensure proper sealing of all equipment access doors within the protected space.
8. Provide airlocks at all entrances to the room (8 ft. long where possible) and construct
them such that the first door closes before the second door opens.
9. Install weatherstripping around door perimeters, provide sweeps and thresholds at the
bottom of all doors and caulk all door and window frames.
10. Provide automatic door closures with sufficient force to provide a good seal.
11. Turn non-airlock doors into emergency exits and remove external hardware where
possible.
12. Seal all cable entries, conduit penetrations and terminations, duct penetrations and all
openings with fire rated sealant.
13. Seal all floor to wall, ceiling to wall and wall to wall joints.
14. Use glazed tile, glazed block, poured concrete or masonry block coated with low
permeability paint walls.
15. Install a differential pressure gauge in each room to monitor the pressure.
16. Remove laboratories, fume hoods, sinks and testing from all protected rooms.
17. Do not access restrooms, break rooms or storage rooms from the protected area.
18. Any room exhaust must be compensated by pressurization air from the Vapor
Adsorber.
19. Prohibit the use and storage of all chemicals within the protected space.
20. Do not locate backup power batteries or emergency generators in the protected area.
21. Prohibit all eating, drinking and smoking in the control room.
22. Restrict room access to authorized personnel only.
23. Place a large warning label on all entrances to remind personnel of the importance of
maintaining the protection of the control room.
24. Develop and implement an inspection list for maintaining the protected space.
25. Perform periodic monitoring of the corrosion level in the control room.
26. Replace the Vapor Adsorber carbon media prior to its depletion.

Compounding Rectal Dosage Forms,

d.
INTRODUCTION
Rectal administration is not often the first route of choice; but it
becomes a good alternative when the oral route is inadvisable. Relatively
low cost and lack of technical difficulties make rectal drug
administration attractive when compared to parenteral therapy.
The downside of rectal administration includes the esthetics and
stigma of violating the patient’s dignity. This, along with potential
rectal irritation due to frequent administration, and difficulty in
titrating a correct dose due to limited strengths of commercial rectal
dosage forms pose some challenges.
Psychologically, rectal dosage forms can provide a considerable
placebo effect in the treatment of anorectal disorders. The user
feels that something is really being done at the involved site and
this can produce a positive attitude towards this mode of treatment
of the disease or disorder. This may promote hope and the
possibility of avoiding the embarrassment of telling the family and
friends of what is happening in the private area.
Previously, the rectal pathway was reserved for the administration
of locally active products such as those in the treatment of hemor-
Quest Educational Services Inc. is accredited by the
Accreditation Council for Pharmacy Education as a
provider of continuing pharmaceutical education.
ACPE No. 748-000-06-003-H01
This lesson is no longer valid for CE credit after 12/01/09.
GOALS AND OBJECTIVES
Goal: To provide information and support for dosage forms that can be compounded and administered rectally.
Objectives: After reading and studying the article, the reader will be able to:
1.List at least five advantages to the rectal administration of drugs.
2.Describe the anatomy and physiology of the rectum.
3.Discuss the factors involved in drug release from different matrices administered rectally.
4.Discuss the characteristics of enemas, microenemas, gels, ointments and aerosols administered rectally.
5.Describe the formulation variables that must be considered in compounding rectal dosage forms.
Compounding Rectal Dosage Forms, Part I
Loyd V. Allen, Jr., Ph.D., R.Ph.
! Professor Emeritus, University of Oklahoma College of Pharmacy
! Editor in Chief, International Journal of Pharmaceutical Compounding
! Dr. Allen is not affiliated with Paddock Laboratories Inc.
rhoids, worms and constipation. In the treatment of hemorrhoids
and anal fissures, a suggestion was made at one time that a suppository
should be “hour glass” or “collar button” shaped so that
the suppository would stay in the anal canal.
Now, it is well accepted that many active ingredients can be administered
rectally and achieve therapeutic blood levels from any of
several different dosage forms. Some medications are best administered
by this route while others can be if needed.
Advantages to Rectal Administration:
The advantages to rectal administration include the following.
1. First pass effect - Avoiding, at least partially, the first pass
effect which may result in higher blood levels for those
drugs subject to extensive first pass metabolism upon oral
administration.
2. Drug stability - Avoiding the breakdown of certain drugs
that are susceptible to gastric degradation.
3. Large dose drugs - Ability to administer somewhat larger
doses of drugs than using oral administration.
4. Irritating drugs - Ability to administer drugs which may
have an irritating effect on the oral or GI mucosa when
administered orally.
5. Unpleasant tasting or smelling drugs - Ability to administer
unpleasant tasting or smelling drugs whose oral
administration is limited.
6. In children, the rectal route is especially useful. An ill child
may refuse oral medication and may fear injections.
7. Rectal administration can be especially useful in terminal
care.
fore the pH of the medium may be determined by the characteristics
of the drug and the dosage form.
FORMULATION VARIABLES
Active drugs have a number of physical characteristics that can
affect efficacy. For rectal dosage forms, those of interest involve the
following:
1. The nature and form of the active principle (esters, salts,
complexes, etc).
2. The physical state, particle dimensions and the specific
surface of the product.
3. The presence or absence of adjuvants added to the active
principle.
4. The nature and type of dosage form in which the active
principle is incorporated.
5. Pharmaceutical procedures used in the preparation of the
dosage form.
Physical State: An active drug can be either a solid, liquid or semisolid
in nature. For solids, the drug’s particle size may be very
important, especially if the drug is not very water soluble; the
increase in surface area resulting from decreased particle size can
serve to enhance its activity.
Solubility: Whether or not the active ingredient is soluble in the
vehicle can alter the manufacturing and compounding processes in
several ways. Increased solubility of the active in the base can
improve product homogeneity; however, it may also delay the
release of the active if there is too great an affinity of the drug for
the vehicle. In some cases, it may be desired to retain the drug in the
rectal cavity for a longer time and this can be accomplished if the
drug has a greater affinity for the vehicle than for migrating to the
mucosal surface for absorption or to produce a local effect.
If the active ingredient is insoluble in the vehicle, as is the case
when a “suspension” or “emulsion” is formed, this poses different
problems. It is necessary to maintain homogeneity of the total mixture;
this can usually be obtained by constant agitation of the
mixture during processing and filling. Emulsions can be handled
through the proper use of surfactants to obtain a homogenous mixture.
Related to the water solubility of a drug can be the rate of diffusion
across the rectal membrane. A drug with high water solubility
quickly leaves the vehicle, producing a high concentration in the
intrarectal phase which supports a high diffusion rate across the
barrier. A drug with low water solubility saturates the intrarectal
phase at a low concentration resulting in low diffusion and subsequent
low dissolution of the drug particles remaining in the melted
excipient. Drugs with low solubility in water may result in low
availability, while drugs with good solubility may give a rapid and
intense therapeutic response with the dose administered.1
A number of factors affect the decisions the pharmacist must make
when preparing a rectal dosage form. Questions the pharmacist
should ask before formulating this dosage form include the following:
! Is the desired effect to result from systemic or local use?
! Is the dosage form a liquid, semisolid or solid?
! Is a rapid or a slow and prolonged release of the
medication desired?
Drugs for local effect may include the treatment of hemorrhoids,
local anesthetics, antiseptics, antibiotics, and antifungals. Drugs for
systemic effect include analgesics, antiasthmatics, antinauseants,
antiepileptics, hormones and others.
The selection of a vehicle is dependent upon a number of physicochemical
variables, including the characteristics of the drug, the
base and other excipients that are present.
Rectal administration provides for a rapid, and in many cases,
extensive absorption of the active ingredient. The rapidity, intensity
and duration of action are three parameters which must be considered
during formulation for rectal administration and, in many
cases, can be altered to meet the needs of the individual patient.
Anatomical and Physiological Considerations
The rectum consists of the last few inches of the large intestine, terminating
at the anus. The wall of the GI tract consists of several
layers, including the mucosa, submucosa, tunica muscularis and the
visceral peritoneum. The mucous membrane of the rectum, where
rectal dosage forms are generally administered, is made up of a
layer of cylindrical epithelial cells, differentiated from those of the
intestine by the absence of villi.
The rectum contains three types of hemorrhoidal veins, namely the
superior hemorrhoidal vein, middle hemorrhoidal vein, and the
inferior hemorrhoidal vein. These veins act by transporting the
active principle absorbed in the rectum to the blood system either
directly by means of iliac veins and the vena cava (inferior and middle
hemorrhoidal veins) or indirectly by means of the portal vein
and the liver (superior hemorrhoidal vein).
The three hemorrhoidal veins are linked by an anastomosis network.
Since it is not really possible to predict the position or exact
location of the dosage form in the rectum, it is not really possible to
predict exactly which way the active principle will be transported. It
may preferably be by one pathway or another or a combination.
However, it is generally accepted that at least 50% to 70% of the
active ingredients administered rectally take the direct pathway,
thus bypassing the liver and avoiding the first-pass effect. There is
also the possibility of absorption into the lymphatic vessels that
should not be dismissed, but may be minimal.
Physiology
The physiological factors likely to affect rectal absorption are the rectal
liquid pH and the rectal liquid buffering capacity. The rectal
mucosal fluid has a pH very close to neutral and has a low buffer
capacity. Hence, after administration of the suppository, the pH of
the rectal liquid may be determined by the active principle being
used. These facts lead us to conclude that the addition of buffering
agents of a suitable pH range to the suppositories could, in some
cases, increase active principle absorption.
When empty of fecal material, the rectum contains only 2 to 3 mL of
inert mucosal fluid. In the resting state, the rectum is nonmotile and
there are no villi or microvilli present on the rectal mucosa. However,
there is abundant vascularization of the submucosal region of the
rectum wall with blood and lymphatic vessels.
Among the physiologic factors that affect drug absorption from the
rectum are the colonic contents, circulation route, and the pH and
lack of buffering capacity of the rectal fluids.
Colonic Content: When systemic effects are desired from the
administration of a medication, greater absorption may be expected
from a rectum that is void than from one that is distended with fecal
matter. A drug will obviously have greater opportunity to make
contact with the absorbing surface of the rectum and colon in the
absence of fecal matter. Therefore, when deemed desirable, an evacuant
enema may be administered and allowed to act before
administration of a suppository of a drug to be absorbed. Other conditions
such as diarrhea, colonic obstruction due to tumorous
growths, and tissue dehydration can all influence the rate and
degree of drug absorption from the rectal site.
Circulation route: It is estimated that about 50-70% of the dose of a
rectal dosage form that is absorbed will bypass the liver into the
general circulation.
pH and Lack of Buffering Capacity of the Rectal Fluids: Because
rectal fluids are essentially neutral in pH (7–8) and have negligible
buffer capacity, the form in which the drug is administered will not
generally be chemically changed by the rectal environment; there-
Drug Release: The rate of drug release is an important factor in the
selection of a vehicle. If a drug does not release its medication
within 6 hours, the patient may not receive its full benefit, as the
drug remaining in the rectum may be expelled. Thus, among the
factors that must be considered in the selection of a suppository
base is the drug’s solubility. One way to ensure maximum release
of the drug from the base is to apply the principle of opposite characteristics,
i.e., water soluble drugs should be placed in oil soluble
bases while oil soluble drugs should be placed in water soluble
bases.
Drug release rate requirements are especially important in the
selection of the suppository base. Other factors must also be considered
when preparing a suppository. They include the presence
of water, hygroscopicity, viscosity, brittleness, density, volume
contraction, special problems, incompatibilities, pharmacokinetics,
and bioequivalence.
Presence of Water: When preparing nonaqueous rectal dosage
forms, the pharmacist should avoid using water to incorporate an
active drug as water may accelerate the oxidation of fat, increase
the degradation rate of many drugs, enhance reactions between
the drug and other components, support bacterial/fungal growth,
and require the addition of bacteriostatic agents. Furthermore, if
the water evaporates, the dissolved substances may crystallize and
possibly become irritating upon insertion.
Hygroscopicity: Glycerin and polyethylene glycol containing
vehicles are hygroscopic. The rate of moisture change is dependent
on the chain length of the molecule as well as the temperature and
humidity of the environment.
Viscosity: Viscosity considerations are also important in the
preparation and the release of the drug. If the viscosity of a base is
low, it may be necessary to add a thickening agent to ensure uniformity
of the drug in the vehicle. After the dosage form has been
administered, the release rate of the drug may be slowed if the viscosity
of the vehicle is very high. This is because the viscosity
causes the drug to diffuse more slowly through the base to reach
the mucosal membrane for absorption.
Brittleness: Brittle suppositories can be difficult to handle, wrap,
and use. In general, brittleness results when the percentage of nonbase
materials exceeds about 30%. Synthetic fat bases with high
stearate concentrations or those that are highly hydrogenated are
typically more brittle. Shock cooling also causes fat and cocoa butter
suppositories to crack. This condition can be prevented by
ensuring that the temperature of the mold is as close to the temperature
of the melted base as possible. Suppositories should not
be placed in a freezer, which also causes shock cooling. The addition
of a small quantity (usually less than 2%) of Tween 80, Tween
85, fatty acid monoglycerides, castor oil, glycerin, or propylene
glycol will make these bases more pliable and less brittle.
ENEMAS/MICROENEMAS
(SOLUTIONS/SUSPENSIONS)
Enemas
Enemas are dosage forms designed to be administered rectally for
clearing out the bowel or for administration of drugs or food. An
enema is a method of administration and may involve solutions,
suspensions, emulsions, foams, and gels. Generally, there are two
types: retention enemas and evacuation enemas.
Retention Enemas: A number of solutions, suspensions and emulsions
are administered rectally for the local effects of the medication
(e.g., hydrocortisone) or for systemic absorption (e.g., aminophylline).
In the case of aminophylline, the rectal route of
administration minimizes the undesirable gastrointestinal reactions
associated with oral therapy. Clinically effective blood levels of the
agents are usually obtained within 30 minutes following rectal
instillation. Corticosteroids can be administered as retention enemas
as adjunctive treatment of some patients with ulcerative colitis.
Evacuation Enemas: Rectal enemas are used to cleanse the bowel.
Commercially, many enemas are available in disposable plastic
squeeze bottles containing a premeasured amount of enema solution.
The agents present are solutions of sodium phosphate and sodium
biphosphate, glycerin and docusate potassium, and light mineral oil.
Enemas may be prepared as solutions, suspensions, emulsions etc.
Solutions: Considerations in preparing solutions include solubility,
solvent selection, pH, osmolality and stability of the drug. If the pH is
too low or too high, it may be irritating to the mucosa. If the solution is
hyperosmolar, it may pull fluids from the local area and initiate a defecation
reflex.
Suspensions: Suspensions are preparations containing finely divided
drug particles distributed somewhat uniformly throughout a vehicle in
which the drug exhibits a minimum degree of solubility. In most good
pharmaceutical suspensions, the particle diameter is between 1 and 50
microns. The pharmacist may have to use a solid dosage form, e.g.,
tablet, capsule, of the drug and extemporaneously compound a liquid
preparation, or it can be made from the bulk powder.
Typically, when formulating an extemporaneous suspension, the contents
of a capsule, crushed tablets, or bulk powder is placed in a
mortar. The selected vehicle is then slowly added to and mixed with
the powder to create a paste and then diluted to the desired volume.
To minimize stability problems of the extemporaneously prepared
product, it should be placed in air-tight, light-resistant containers by
the pharmacist and subsequently stored in the refrigerator by the
patient. Because it is a suspension, the patient should be instructed to
shake it well prior to use and on a daily basis watch for any color
change or consistency change that might indicate a stability problem
with the formulation.
The following examples of rectal suspensions have frequently been
compounded by pharmacists when not commercially available. Barium
Sulfate for Suspension, USP has been employed orally or rectally
for the diagnostic visualization of the gastrointestinal tract.
Mesalamine (i.e., 5-aminosalicylic acid) suspension was introduced
onto the market in 1988 as Rowasa® (Solvay) for treatment of Crohn’s
disease, distal ulcerative colitis, proctosigmoiditis, and proctitis.
Emulsions: An emulsion is a dispersion in which the dispersed phase
is composed of small globules of a liquid distributed throughout a
vehicle in which it is immiscible. Pharmaceutically, the process of
emulsification enables the pharmacist to prepare relatively stable and
homogeneous mixtures of two immiscible liquids. It permits the
administration of a liquid drug in the form of minute globules rather
than in bulk.
The initial step in preparation of an emulsion is the selection of the
emulsifier. Among the emulsifiers and stabilizers for pharmaceutical
systems are some carbohydrate materials (acacia, tragacanth, agar,
chondrus, and pectin), protein substances (gelatin, egg yolk, and
casein), high molecular weight alcohols (stearyl alcohol, cetyl alcohol,
and glyceryl monostearate), wetting agents (which may be anionic,
cationic, or nonionic), and finely divided solids (colloidal clays including
bentonite, magnesium hydroxide, and aluminum hydroxide).
Emulsions may be prepared by several methods, depending upon the
nature of the emulsion components and the equipment available for
use. On a small scale, as in the laboratory or pharmacy, emulsions may
be prepared using a dry Wedgewood or porcelain mortar and pestle, a
mechanical blender or mixer such as a Waring blender or a milk-shake
mixer, a hand homogenizer, a bench-type homogenizer, or sometimes
a simple prescription bottle. On a large scale, large volume mixing
tanks may be used to form the emulsion through the action of a highspeed
impeller. As desired, the product may be rendered finer by
passage through a colloid mill, in which the particles are sheared
between the small gap separating a high speed rotor and the stator, or
by passage through a large homogenizer, in which the liquid is forced
under great pressure through a small valve opening.
Microenemas
A microenema, also called rectal tube, is a more concentrated
form of a drug generally administered for a systemic effect. As
an example, diazepam microenemas (Stesolid® in Europe) are
available, generally containing about 5 mg/mL diazepam in
solution. Diazepam microenemas are generally used in the management
of selected, refractory patients with epilepsy, on stable
regimens of antiepileptic drugs, who require intermittent use of
diazepam to control occasional breakthrough seizures.
Microenemas can be easily prepared by adding thickening
agents to injectable solutions. This provides the dose of a drug
in a reasonably small volume of generally 1 to 5 mL. Microenemas
can be administered by attaching a short length of tubing to
a syringe in which the microenema has been placed. The tubing
is lubricated and inserted rectally, followed by depressing the
plunger to deliver the drug. As an alternative, the microenema
can be placed in a plastic bulb-device where the tip is lubricated
and then inserted rectally and the bulb squeezed to expel the
drug.
GELS
Gels are semisolid systems consisting of dispersions made up of
either small inorganic particles or large organic molecules
enclosing and interpenetrated by a liquid. Some gel systems are
as clear as water in appearance and others are turbid, since the
ingredients involved may not be completely molecularly dispersed
(soluble or insoluble) or they may form aggregates,
which disperse light. The concentration of the gelling agents is
mostly less than 10%, usually in 0.5 to 2.0% range, with some
exceptions.
Gels may be prepared by the direct hydration in water of the
inorganic chemical, the hydrated form constituting the disperse
phase of the dispersion. Examples of gelling agents include acacia,
alginic acid, bentonite, carbomer, carboxymethylcellulose
sodium, cetostearyl alcohol, colloidal silicon dioxide, ethylcellulose,
gelatin, guar gum, hydroxyethylcellulose, hydroxypropyl
cellulose, hydroxypropyl methylcellulose, magnesium aluminum
silicate, maltodextrin, methylcellulose, polyvinyl
alcohol, povidone, propylene carbonate, propylene glycol alginate,
sodium alginate, sodium starch glycolate, starch,
tragacanth and xanthan gum.
In gel preparation, the powdered polymers, when added to
water, may form temporary gels that slow the process of dissolution.
As water diffuses into these loose clumps of powder,
their exteriors frequently turn into clumps of solvated particles
encasing dry powder. The globs or clumps of gel dissolve very
slowly because of their high viscosity and low diffusion coefficient
of the macromolecules.
Rectal lubricating jellies are used to assist in medical procedures,
to aid in insertion of various devices and drugs, including
catheters and suppositories, and as vehicles for some drug products,
especially in extemporaneous compounding.
RECTAL OINTMENTS
The use of rectal ointments is generally limited to the treatment
of local conditions. Ointments can be for topical application to
the perianal area and for insertion within the anal canal. They
mostly are used to treat local conditions of anorectal pruritus,
inflammation and the pain and discomfort associated with hemorrhoids.
The drugs employed include astringents (e.g., zinc
oxide), protectants and lubricants (e.g., cocoa butter, lanolin),
local anesthetics (e.g., pramoxine HCl), and antipruritics and
anti-inflammatory agents (e.g., hydrocortisone).
The bases used in anorectal ointments and creams include combinations
of polyethylene glycol 300 and 3350, emulsion cream
bases utilizing cetyl alcohol and cetyl esters wax, and white
petrolatum and mineral oil. When antimicrobial preservatives
are required, methylparaben, propylparaben, benzyl alcohol,
and butylated hydroxyanisole (BHA) are frequently used.
Before applying rectal ointments and creams to the perianal
skin, the affected area should be cleansed and dried by gentle
patting with toilet tissue. Then a portion of the ointment or
cream is placed on a tissue and a thin film is gently spread over
the affected area. Products having a water-washable base are
easier to spread and remove after application and tend to stain
clothing less than products having an oleaginous base.
Rectal ointments and creams may be dispensed with special
perforated plastic tips for products to be administered into the
anus, primarily in the treatment of the pain and inflammation
associated with hemorrhoids. Before use, the rectal tip should
be thoroughly cleaned, screwed onto the ointment tube in place
of the cap, and lubricated with mineral oil or a lubricating jelly.
Anusol® and Tronolane® are examples of rectal ointments used
in the treatment of hemorrhoids.
Aerosols
Although occassionally used rectally, these are not generally
suitable for compounding. Pharmaceutical aerosols are pressurized
dosage forms containing one or more active ingredients
which upon actuation emit a fine dispersion of liquid and/or
solid materials in a gaseous medium. Pharmaceutical aerosols
are similar to other dosage forms because they require the same
types of considerations with respect to formulation, product stability,
and therapeutic efficacy. However, they differ from most
other dosage forms in their dependence upon the function of the
container, its valve assembly, and an added component—the
propellant—for the physical delivery of the medication in proper
form.
Aerosol products may be designed to expel their contents as a
fine mist, a coarse, wet or a dry spray, a steady stream, or as a
stable or a fast-breaking rectal foam. The physical form selected
for a given aerosol is based on the intended use of that product.
Rectal Aerosols
Rectal aerosol foams are commercially available containing antiinflammatory
agents. The aerosol package contains an inserter
device used to direct the foam when activated. The foams are
generally oil-in-water emulsions, resembling light creams.
Some available commercial preparations of rectal foams use rectal
inserters for the presentation of the foam to the anal canal.
Products such as ProctoFoam® (pramoxine hydrochloride) and
Proctofoam®-HC (with hydrocortisone) are used to relieve
inflammatory anorectal disorders. These products are accompanied
by applicators to facilitate administration. When ready to
use, the applicator is attached to the aerosol container and filled
with a measured dose of product. The applicator is then inserted
into the anus and the product delivered by pushing the
plunger of the applicator. After removal, the applicator and the
patient’s hands should be thoroughly washed.
COMPOUNDING FORMULAS
ENEMAS/MICROENEMASSOLUTIONS/
SUSPENSIONS/EMULSIONS
Diazepam 5 mg/mL Rectal Microenema
Diazepam 500 mg
Ethanol 95% 10 mL
Benzoic acid 0.1 gm
Sodium benzoate 4.9 gm
Benzyl alcohol 1.5 mL
Propylene glycol 40 mL
Hydroxypropyl methylcellulose 4.2 gm
Purified water qs 100 mL
Mix the ethanol, propylene glycol and benzyl alcohol together.
Add the diazepam and mix until dissolved. Add the hydroxypropyl
methylcellulose and mix until dispersed well. Mix the
sodium benzoate and benzoic acid in about 40 mL of purified
water. Slowly, add this mixture to the propylene glycol mixture
and mix well. Add sufficient purified water to volume, mix well,
and allow to stand until the solution is thickened. Package and
label.
Incorporate the micronized hydrocortisone into the methylcellulose
solution and mix well. Add sufficient preserved water to
volume and mix well. Package and label.
Wet the povidone with about 15 mL of water to form a paste. Use
a magnetic stirrer and add about 60 mL of water, stirring until a
clear solution is obtained. Add the micronized progesterone and
mix well. Add the remaining water to volume and thoroughly
mix. Package and label.
Dissolve the short-chain fatty acids and sodium chloride in about
90 mL of the purified water. Check and adjust the pH if necessary
using either 10% sodium hydroxide solution or 10% hydrochloric
acid to a pH between 7 and 8. Add sufficient purified water to volume
and mix well. Package and label.
Dissolve the monobasic and dibasic sodium phosphate in sufficient
purified water to volume. Package and label.
Mix the sulfasalazine with the glycerin to form a smooth paste.
Geometrically, incorporate the methylcellulose 2% solution to volume
and mix well. Package and label.
GELS
Combine the diltiazem hydrochloride with the propylene glycol
and mix to form a smooth paste. Incorporate the
hydroxyethylcellulose and mix well. Heat the preserved
water to about 70° C and slowly incorporate into the propylene
glycol mixture and mix well. Package and label.
Combine the nifedipine with the diethylene glycol monoethyl
ether to form a smooth paste. Add the lecithin:isopropyl
palmitate solution and mix well. Add sufficient Pluronic F-
127 20% gel to volume and mix thoroughly, using a
mechanical shearing force. Package and label.
Disperse the methylcellulose in 40 mL of hot (80–90° C) water.
Chill overnight in a refrigerator to effect solution. Disperse
the Carbopol 934 in 20 mL water. Adjust the pH of the dispersion
to 7.0 by adding sufficient 1% sodium hydroxide
solution (about 12 mL is required) and bring the volume to
40 mL with purified water. Dissolve the methylparaben in the
propylene glycol. Mix the methylcellulose, Carbopol 934 and
propylene glycol fractions using caution to avoid incorporating
air. Package and label.
OINTMENTS
Mix the anhydous lanolin with the white petrolatum.
Geometrically, incorporate the lanolin-white petrolaum mixture
into the nitroglycerin 2% ointment and mix until
uniform. Package and label.
REFERENCES
1. Readldon N, Ragazzi E, Ragazzi E. Effect of drug solubility
on the in vitro availability rate from suppositories with
lipophilic excipients. Pharmazie. 2000 May;55(5):372-7.
Sodium Phosphate Enema Solution
Sodium phosphate, dibasic, anhydrous 19 g
Sodium phosphate, monobasic, anhydrous 7 g
Purified water qs 118 mL
Sulfasalazine Enema
Sulfasalazine 3 g
Glycerin 5 mL
Methylcellulose 2% solution qs 50 mL
Diltiazem Hydrochloride 2% Gel
Diltiazem hydrochloride 2 g
Propylene glycol 10 mL
Hydroxyethylcellulose 2 g
Preserved water qs 100 mL
Nifedipine Gel 160 mg/mL in PLO
Nifedipine 16 g
Diethylene glycol monoethyl ether 10 mL
Lecithin:isopropyl palmitate solution 20 mL
Pluronic F-127 20% gel qs 100 mL
Rectal Lubricating Jelly Formula
Methylcellulose, 4000 cps 0.8 gm
Carbopol 934 0.24 gm
Propylene glycol 16.7 mL
Methylparaben 0.015 gm
Sodium hydroxide, qs ad pH 7
Purified water, qs ad 100 gm
Nitroglycerin 0.2% Ointment
Nitroglycerin 2% ointment 10 g
Lanolin, anhydrous 30 g
White petrolatum 60 g
Hydrocortisone 100 mg Enema
Hydrocortisone, micronized 100 mg
Methylcellulose 2% solution 25 mL
Preserved water qs 50 mL
Progesterone 200 mg per 100 mL Enema
Progesterone, micronized 200 mg
Povidone 10 g
Purified water qs 100 mL
Short Chain Fatty Acid Enema
Sodium acetate, trihydrate 817 mg
Sodium propionate 288 mg
Sodium butyrate 440 mg
Sodium chloride 82 mg
Purified water qs 100 mL
7. Which of the following characteristics may help in increasing the rate of drug
absorption?
I. insoluble in the vehicle
II. soluble in rectal fluids
III. very viscous vehicle
A. I only
B. III only
C. I and II only
D. II and III only
E. I, II and III.
8. How can viscosity affect a rectal dosage form?
I. If too high, drug release may be slow
II. Is needed to help ensure uniformity of suspensions during preparation
III. Helps minimize degradation of the drug
A. I only
B. III only
C. I and II only
D. II and III only
E. I, II and III.
9. Which of the following ingredients are commonly used intrarectally and
around the rectal opening?
A. bismuth subnitrate
B. diazepam
C. hydrocortisone
D. progesterone
E. methotrexate
10.Microenemas generally consist of the drug in a volume of about:
A. 1-5 mL
B. 5-10 mL
C. 10-15 mL
D. 15-25 mL
E. 25-50 mL
11. My practice setting is:
A. Community-based C. Hospital-based
B. Managed care-based D. Consultant and other
12. The quality of the information presented in this article was:
A. Excellent B. Good C. Fair D. Poor
13. The test questions correspond well with the information presented.
A. Yes B. No
14. Approximately how long did it take you to read the Secundum Artem
article AND respond to the test questions?
15. What topics would you like to see in future issues of Secundum Artem?
1. When administered rectally, at least what percent of the active ingredients will
avoid the first-pass effect?
A. Less than 10%
B. 10-25%
C. 25-50%
D. 50-70%
E. More than 70%
2. Which of the following factors can affect the efficacy of a rectally administered
dosage form?
I. whether the drug is an ester, salt, or complex
II. the presence of adjuvants in the formula
III. the particle size of the drug
A. I only
B. III only
C. I and II only
D. II and III only
E. I, II and III.
3. Generally, it is best to keep water out of a fatty acid base suppository rectal
dosage form because:
I. it may accelerate oxidation of fat
II. it may increase the degradation rate of drugs
III. it may support bacterial/fungal growth
A. I only
B. III only
C. I and II only
D. II and III only
E. I, II and III.
4. Microenemas can be easily prepared by adding what ingredient to an injection?
A. buffering agent
B. chelating agent
C. preservative
D. surfactant
E. thickening agent
5. Alginic acid, carbomer, cetostearyl alcohol, hydroxypropyl cellulose,
magnesium alminum silicate and povidone are all agents that can be used as:
A. buffering agents
B. chelating agents
C. preservatives
D. surfactants
E. gelling agents
6. Which of the following dosage forms can be used to produce a systemic effect
of an active drug?
A. rectal enema
B. rectal gel
C. rectal ointment
D. rectal microenema
E. all the above

DEFINITIONS Some important terms

used in this guideline are defined below. They may have different meanings in
other contexts.
Bioavailability
The rate and extent to which the active moiety is absorbed from a pharmaceutical dosage form and
becomes available at the site(s) of action. In the majority of cases reliable measurements of drug


concentrations at the site(s) of action are not possible. The substance in general circulation, however, is
considered to be in equilibrium with the substance at the site(s) of action. Bioavailability can be
therefore defined as the rate and extent to which the active pharmaceutical ingredient or active
moiety is absorbed from a pharmaceutical dosage form and becomes available in the general
circulation. It is assumed by PK-PD theory that in the same subject an essentially similar plasma
concentration time course will result in an essentially similar concentration time course at the site(s)
of action.
Bioequivalence
Two pharmaceutical products are bioequivalent if they are pharmaceutically equivalent or
pharmaceutical alternatives and their bioavialbility in terms of peak (Cmax and Tmax) and total
exposure (AUC) after administration of the same molar dose under the same conditions are similar to
such a degree that their effects can be expected to be essentially the same. Bioequivalence focuses on
the equivalence of release of the active pharmaceutical ingredient from the pharmaceutical product
and its subsequent absorption into the systemic circulation.
Biopharmaceutics Classification System (BCS)
BCS is a scientific framework for classifying active pharmaceutical ingredients based upon their
aqueous solubility and intestinal permeability. When combined with the dissolution of the
pharmaceutical product, the BCS takes into account three major factors that govern the rate and extent
of drug absorption (exposure) from immediate release oral solid dosage forms: dissolution, solubility,
and intestinal permeability.
Biowaiver
The term biowaiver is applied to a regulatory drug approval process when the dossier (application) is
approved based on evidence of equivalence other than in vivo bioequivalence test.
Comparator product
Comparator product is a pharmaceutical product with which the new multisource product is intended
to be interchangeable in clinical practice. The comparator product will normally be the innovator
product for which efficacy, safety and quality has been established. The selection of the comparator
product is usually made at the national level by the drug regulatory authority. A national drug
regulatory authority has in principle options which are described in section 6.5.2.
Dosage form
The finished formulation of a pharmaceutical product, e.g. tablet, capsule, suspension, solution for
injection, suppository.
Equivalence requirements
In vivo and/or in vitro testing requirements for multisource pharmaceutical product approval and
marketing authorization.
Equivalence test
Equivalence test is a test that determines the equivalence between the multisource product and the
comparator product using in vivo and/or in vitro approaches.
Fixed-dose combination (FDC)
A combination of two or more active pharmaceutical ingredients in a fixed ratio of doses.
This term is used generically to mean a particular combination of active pharmaceutical


ingredients irrespective of the formulation or brand. It may be administered as single entity
products given concurrently or as a finished pharmaceutical product.
Fixed-dose combination finished pharmaceutical product (FDC-FPP)
A finished pharmaceutical product that contains two or more active pharmaceutical ingredients.
Generic product
A “generic product” is a multisource pharmaceutical product which is intended to be interchangeable
with the comparator product. It is usually manufactured without a licence from the innovator
company and marketed after the expiry of patent or other exclusivity rights.
[Note from the WHO Secretariat:
WHO's Legal Department has commented that the use of the word "usually" in the
definition of generic product is not favoured. Please comment.]
Innovator pharmaceutical product
Generally, the innovator pharmaceutical product is that which was first authorized for marketing, on
the basis of documentation of quality, safety and efficacy.
Interchangeable pharmaceutical product
An interchangeable pharmaceutical product is one which is therapeutically equivalent to a
comparator product and can be interchanged in clinical practice.
In vitro equivalence test
In vitro equivalence test is a dissolution test that includes dissolution profiles comparison between the
multisource product and the comparator product in three media: pH1.2 HCl, pH 4.5 and pH 6.8.
In vitro quality control dissolution test
Dissolution test procedure identified in the pharmacopoeia, generally a one time point dissolution test
for immediate release products and three or more time points dissolution test for modified release
products.
Multisource pharmaceutical products
Multisource pharmaceutical products are intended to be pharmaceutically equivalent or
pharmaceutical alternatives that are bioequivalent and hence are therapeutically equivalent and
interchangeable.
Pharmaceutical alternatives
Products are parmaceutical alternative (s) if they contain the same molar amount of the same active
pharmaceutical moiety(s) but differ in dosage form (e.g. tablets versus capsules), and/or chemical
form (e.g. different salts, different esters). Pharmaceutical alternatives deliver the same active moiety
by the same route of administration but are otherwise not pharmaceutically equivalent. They may or
may not be bioequivalent or therapeutically equivalent with the comparator product.
Pharmaceutical equivalence
Products are pharmaceutical equivalents if they contain the same molar amount of the same active
pharmaceutical ingredient(s) in the same dosage form that meet the same or comparable standards
and are intended to be administered by the same route. However, pharmaceutical equivalence does
not necessarily imply bioequivalence and therapeutic equivalence, as differences in the excipients
and/or the manufacturing process can lead to differences in product performance.

Therapeutic equivalence
Two pharmaceutical products are considered to be therapeutically equivalent if they are
pharmaceutically equivalent or pharmaceutical alternatives and after administration in the same
molar dose, their effects, with respect to both efficacy and safety, will be essentially the same when
administered to patients by the same route under the conditions specified in the labelling. This can be
demonstrated by appropriate bioequivalence studies such as pharmacokinetic, pharmacodynamic,
clinical or in vitro studies.

Aluminum ibuprofen pharmaceutical suspensions

INTRODUCTION

This invention relates to pharmaceutical compositions of aluminum salts of ibuprofen. More particularly, this invention provides new gel-resistant, non-caking, liquid pharmaceutical suspensions of aluminum ibuprofen which are easily shakable to a homogeneous consistency for uniform dosing and which have improved resistance to dissolution rate reduction upon storage.

BACKGROUND OF THE INVENTION

Nicholson et al. U.S. Pat. No. 3,385,886 claims 2-(4-isobutylphenyl)propionic acid (ibuprofen) as a compound per se. Nicholson et al. U.S. Pat. No. 3,228,831 discloses the use of ibuprofen as a drug to alleviate the symptoms of inflammation in animals. Since its introduction as a commercially available drug for human use, there has been much medical literature about ibuprofen. Ibuprofen is sold as coated tablets because ibuprofen per se has a bitter, sharply disagreeable taste. The distinct acid taste of ibuprofen is masked by the coating which permits oral administration without giving the bitter or burning acid taste of the free acid. Continued research for better modes in which to administer ibuprofen continues for the purposes of eliminating or reducing the cost of and the need for coatings presently used to overcome as much as possible the disagreeable acid taste of ibuprofen.

It has been found that the usual sodium, calcium and magnesium salts of this acid also contain a discernible disagreeable taste.

Recently, it was discovered that aluminum salts of ibuprofen provide an essentially tasteless, effective pharmaceutical form of ibuprofen which salts can be manufactured economically and compounded into pharmaceutical liquid suspension and solid formulations for administration in unit dosage forms. These aluminum salts are disclosed and claimed in Sinkula U.S. patent application Ser. No. 640,431, filed Dec. 15, 1975, now abandoned but replaced by application Ser. No. 152,238, filed May 22, 1980.

Aluminum ibuprofen salts are not soluble in water or the other pharmaceutical excipients to any substantial extent and they are difficult to wet and disperse uniformly in liquid mixtures. These salts would normally be compounded into any of various solid dosage forms. However, pharmaceutical liquid suspension forms of these salts would be preferred when the patients are to be small children or elderly persons because these patient populations often have difficulty swallowing tablets, capsules or other solid forms of drugs.

In preparing suspensions of water-insoluble drug compounds such as these aluminum ibuprofen salts, the particular pharmaceutical vehicle or diluent mixture which is best for these salts is not readily predictable from knowledge and experience with other similar drug acid salts. Substitution of an aluminum salt of one drug acid into a pharmaceutical formulation of another aluminum salt of a drug acid does not often produce an acceptable pharmaceutical composition for the dosage use intended. See, for example, Belgian Pat. No. 811,810 and the results obtained comparing that formulation in Fitch/Rowe U.S. Pat. No. 4,145,440, Column 9.

To be an acceptable pharmaceutical product the aluminum ibuprofen salt suspension must have a suitable long shelf life, say, one to three years, the liquid suspension must not gel to any significant extent, the solids in the liquid suspension must not settle to form a hard non-uniformly dispersible cake, and the amount of sedimentation of the solids in the suspension must be controlled to within a range of from about 60 to 95 percent of the suspension liquid volume, preferably to about 70 to 85 percent of the suspension liquid volume.

This invention can be considered to be an improvement on the aluminum ibuprofen pharmaceutical suspensions described and claimed in the Fitch/Rowe U.S. Pat. No. 4,145,440. That Fitch/Rowe '440 Patent described pharmaceutical liquid suspension compositions of aluminum ibuprofen salts which are gel-resistant, non-caking, have controlled sedimentation properties and which are easily re-suspended by shaking the suspension bottle by dispersing the aluminum ibuprofen salt in a sorbitol/glycerin/water mixture containing controlled maximum amounts of pharmaceutically acceptable suspending agents and water-soluble surface active agents. Those Fitch/Rowe '440 Patent compositions can also contain small amounts of ethanol, sorbic acid, and sweetening agents such as sucrose, sodium saccharin, and flavoring and coloring agents. Such patent also includes discussion of using an aluminum ibuprofen salt having a ratio of about two ibuprofen equivalents per atom of aluminum in the salt.

Those Fitch/Rowe '440 Patent compositions are effective when used shortly after preparation thereof. However, unexpectedly, it has been discovered that upon long standing on a shelf at various temperature conditions, a problem with those compositions has been observed, the problem being that such Fitch/Rowe '440 compositions, based as they are on a sorbitol/glycerin mixture as part of the liquid vehicle for the suspension, exhibit an aging property of the resulting composition. This aging property has the effect of reducing the dissolution rate of the active ingredient, the aluminum ibuprofen salt, in the liquid suspension to an unacceptably low percentage level when an extended shelf life (say six months or longer) is required for clinical or market acceptance of the suspension as desired product for use world wide for pediatric and geriatric anti-inflammatory therapy applications, which circumstances often require long storage times under varying temperature environments.

Finding this catalytic effect on aging of the composition by the sorbitol/glycerin components in the composition was surprising because there are pharmaceutical literature references such as "Structure of Aluminum Hydroxide Gel III: Mechanisms of Stabilization by Sorbitol" by Steven L. Nail et al. in Journal of the Pharmaceutical Sciences, Vo. 65, No. 8, August 1976 pgs. 1195-1198, which indicate that sorbitol, added to aluminum hydroxide gels, was effective in preventing the loss of the acid consuming capacity of the gel (less than ten percent loss) during the six month aging periods, compared to the substantial loss (greater than sixty percent loss) of acid consuming capacity of identical gels which did not contain sorbitol. However, in these aluminum ibuprofen pharmaceutical suspensions it has been found, according to this invention, that sorbitol and glycerin, for some reason not yet fully understood, appear to catalyze the aging and to reduce the dissolution rates of aluminum ibuprofen in these pharmaceutical suspensions. Those in the pharmaceutical chemistry sciences and arts continue to need and search for liquid pharmaceutical suspensions of aluminum ibuprofen salts which are not only gel resistant, non-caking, have controlled sedimentation properties and which suspensions are easily resuspended by shaking the suspension bottle, but also for liquid pharmaceutical suspensions which will not contain ingredients which lower to unacceptable levels the dissolution rate properties of the aluminum ibuprofen contained therein during normal storage periods.

OBJECTS OF THE INVENTION

It is an object of this invention to provide new homogeneously dispersible liquid pharmaceutical suspension compositions of aluminum ibuprofen salts, whose compositions have better dissolution rate properties after periods of storage. It is another object of this invention to improve the aging and dissolution rate properties of aluminum ibuprofen liquid pharmaceutical suspension compositions. Other objects, aspects and advantages of this invention will become apparent from the remaining specification and the claims which follow.

SUMMARY OF THE INVENTION

Briefly, according to this invention, it has been discovered that liquid pharmaceutical suspensions satisfying the above objects can be obtained by suspending the aluminum ibuprofen salt active ingredient in a liquid pharmaceutical suspension containing maximum, controlled amounts of micro-crystalline cellulose, sodium carboxy methylcellulose, or magnesium aluminum silicate suspending agents or mixtures thereof and pharmaceutically acceptable water soluble surface active agents in an aqueous vehicle to obviate or remove the aging problem caused by sorbitol and/or glycerin (of the '440 Patent compositions) and thus increase the dissolution rate over longer periods of storage. It has also been discovered that these improved dissolution rates for the aluminum ibuprofen active ingredient are not materially affected by the addition of or presence of up to about 30 grams of sucrose per 100 ml of liquid suspension composition, or equivalent amounts of sweeteners selected from the group consisting of sucrose, fructose, glucose, sodium saccharin, sodium cyclamate, and mixtures thereof, and thus the addition of these particular sweetening agents can materially aid the taste and acceptability of the suspension to pediatric and geriatric patient populations while still permitting and accomplishing the requirement that the suspension be gel resistant, and non-caking, with controlled sedimentation properties and which settled suspension can easily be re-suspended by shaking the suspension bottle, with only minor affects on the dissolution rate property of the aluminum ibuprofen therein.

DETAILED DESCRIPTION OF THE INVENTION

More particularly, this invention provides pharmaceutical liquid suspension compositions comprising, for each 100 ml of suspension,

(a) from about 4 to about 17 grams of an aluminum salt of ibuprofen,

(b) from about 0.2 to about 1.1 grams of pharmaceutically acceptable suspending agent having an average particle size below about 50 microns,

(c) from about 0.3 to about 0.7 grams of a non-toxic, pharmaceutically acceptable essentially water soluble surface active agent, and

(d) sufficient water to bring the liquid volume to 100 ml of total liquid suspension.

In addition, the above mixture is treated, if necessary, with sufficient pharmaceutical grade hydrochloric acid or sodium hydroxide or equivalent acid or base aqueous solution to bring the pH of the suspension to between 4.5 and 5.5, preferably to about 5.0. Usually less than 2 ml of ten percent v/v hydrochloric acid solution are required per 100 ml of suspension.

The above compositions contain no sorbitol or glycerin and no sucrose or other saccharide type sugar. Such compositions pass the dissolution rate tests and are acceptable from the point of view of having long term post storage dissolution rate properties for the aluminum ibuprofen salt therein as well as the other above desired properties. However, such compositions have a flat, chalky taste which is not acceptable to most patients.

Preferred compositions of this invention are those described immediately hereinabove which also contain (e) from 5 to 30 grams of granular U.S.P. sucrose in the described 100 ml of liquid suspension composition. It has been discovered surprisingly that these amounts of sucrose do not significantly affect the higher dissolution rate properties of the liquid suspension compositions which do not contain sorbital or glycerin, after extended storage periods.

The preferred suspending agent (b) is selected from the group consisting of:

(1) a mixture of a major amount of microcrystalline cellulose and a minor amount of sodium carboxymethylcellulose

(2) a magnesium aluminum silicate powder, and

(3) mixtures of (1) and (2), that is, so that the total weight of the suspending agent (1) and (2) mixture is not more than about 1.1 weight percent of the total liquid suspension.

The suspension can also, optionally contain up to about 10 ml of 95 percent ethanol, for each 100 ml of suspension, before the water is added to make the total volume of suspension. The ethanol aids the wetting of the solid ingredients in the suspension.

The composition may also, optionally have added thereto up to about 0.3 mg of sorbic acid, N.F., for each 100 ml of suspension, or other equivalent substance to inhibit the presence, growth and action of mold or yeast.

We have also discovered that in place of part or all of the sucrose, equivalent sweetening amounts of fructose, glucose, sodium saccharin, sodium cyclamate, or mixtures of these sweetening agents can be used without substantially reducing the dissolution rate properties of the aluminum ibuprofen active ingredient therein. Thus, for example, in place of using 5 to 30 grams of sucrose in one of these formulations one can use from about 6.25 grams to about 37.5 grams of glucose, from about 2.94 grams to about 17.65 grams of fructose, from about 5 milligrams to about 60 milligrams of sodium saccharin, from about 166 milligrams to about 1 gram of sodium cyclamate, or equivalent sweetening mixtures of sucrose, glucose, fructose sodium saccharin or sodium cyclamate, as desired.

Examples of flavoring agents which can be included in amounts up to about 1 gram per 100 ml of suspension, include Orange-Lemon Flavor PFC 8432, and other pharmaceutically acceptable flavors, such as Cherry Flavor, Peppermint oil, double distilled eucalyptol, anethol, methyl salicylate, oil cassia or cinnamic aldehyde, and the like.

A preferred composition of all the above generally indicated ingredients according to this invention is one which comprises, for each 100 ml of liquid suspension,

(a) about 4.4 to about 14 grams of an aluminum ibuprofen salt, which will provide about 4 to about 12.7 grams of ibuprofen equivalent in the suspension composition;

(b) about 0.2 to 1.1 grams of a suspending agent mixture consisting of about 0.18 to 1.0 grams of microcrystalline cellulose and about 0.02 to about 0.12 grams of sodium carboxymethylcellulose NF low viscosity;

(c) about 0.3 to about 0.7 grams of a surfactant such as (Z)-sorbitan-mono-9-octadecenoate poly(oxy-1,2-ethanediyl)derivatives such as polyoxethylene (20) sorbitan mono-oleate, known in the trade as Polysorbate 80;

(d) from about 5 to about 30 grams of granular U.S.P. sucrose or its sweetening equivalent of glucose, fructose sodium saccharide, sodium cyclamate, or mixtures thereof.

(e) from about 0.1 to about 0.3 grams of sorbic acid NF;

(f) from about 0.032 to 0.05 ml of artificial Cherry-Vanilla Flavor;

(g) 10 percent v/v hydrochloric acid aq. solution q.s. (for pH adjustment);

(h) 10 percent w/v sodium hydroxide aq. solution q.s. (for pH adjustment)

(i) Purified water q.s. ad to 100 ml.

In a typical preferred aluminum ibuprofen liquid suspension of the above type, that is, an example of a specific liquid suspension composition we use, for each 100 ml of liquid suspension composition,

(a) about 8.8 grams of an aluminum monohydroxy bis(2-(4-isobutylphenyl)propionate salt, referred to herein as a 1:2 aluminum:ibuprofen salt, preferably such a salt, referred to herein as a 1:2 aluminum:ibuprofen salt, preferably such a salt powder having at least 7 square meters of surface area per gram, (8.8 grams of pure anhydrous aluminum ibuprofen, 1:2, will provide 8.0 grams of ibuprofen equivalent when hydrolyzed);

(b) about 0.5 grams of a suspending agent comprising about 89 percent, by weight, microcrystalline cellulose and 11 percent, by weight, of sodium carboxymethylcellulose NF low viscosity, (AVICEL® RC-591);

(c) about 0.5 grams of Polysorbate 80 USP;

(d) about 15 grams of sucrose USP;

(e) about 0.2 grams of sorbic acid NF,

(f) about 0.05 ml of artificial Cherry Vanilla Flavor;

(g) sufficient 10 percent v/v hydrochloric acid aq. solution to bring pH to 5.0, and

(h) Purified water, q.s to 100 ml.

To prepare a liquid suspension composition of the above type, we follow the following procedure:

Add the microcrystalline cellulose and sodium carboxymethylcellulose suspending agent to one-half of the purified water (for the lot size desired) in a tared, calibrated, stainless steel, or equivalent tank. Mix well for thirty minutes. Add the sorbic acid and Polysorbate 80 and mix until dispersed.

Add the sucrose or other sweetening agent and flavor and mix until dispersed.

Add the aluminum ibuprofen salt slowly with rapid mixing while avoiding excess air entrapment. Stir until the mixture is completely wetted, then reduce the mixing speed to a slow roll to release air, until the mixture is a fluid with no foam.

The batch can optionally be allowed to stand overnight at this point, and then stirred again to ensure air removal. When air is sufficiently released, adjust pH to about 5 with the hydrochloric acid and q.s. the mixture with the remaining purified water to the total volume desired. The mixture is passed through a colloid mill to break up aggregates and then stirred slowly to release entrapped air.

The aluminum ibuprofen salt in the suspension is a salt of the formula I where x is 0 to 2, y is 1 to 3, so that the sum of x and y is equal to 3. This formula is intended to include mixtures of mono-ibuprofen aluminum salt, di-ibuprofen aluminum salt and tri-ibuprofen-aluminum salt molecules so that in a typical aluminum salt sample the average ratio of ibuprofen moiety to aluminum atom in the sample can range between, say 0.9 and 2.9. The preferred aluminum ibuprofen salts for use in these compositions are those having an average ratio of between about 1 and 2 ibuprofen acid equivalents per aluminum atom (x=1 to 2; y=1 to 2). We are developing an aluminum ibuprofen suspension of this invention using an aluminum ibuprofen salt which contains an average of about two ibuprofen moieties per atom of aluminum, although aluminum ibuprofen salts containing down to about 1 equivalent of ibuprofen per aluminum atom work very well in these suspensions. Aluminum ibuprofen salts containing close to the maximum ratio of three ibuprofen equivalents per aluminum atom can be used but they are not preferred because they are difficult to purify from adhering ibuprofen, which, as indicated above, contributes to a disagreeable taste and because in aqueous media they hydrolyze partially to hydroxy aluminum ibuprofen salts and free ibuprofen.

The preferred aluminum monohydroxy bis-ibuprofen salt for use in these suspensions can be prepared by the general method of Sinkula, supra, 2[ibuprofen Na+]+AlCl ₃ +NaOH (ibuprofen) ₂ -AlOH+3NaCl where "ibuprofen" denotes the anionic form of 2-(4-isobutylphenyl)propionic acid. Dihydroxy mono-ibuprofen aluminum salt (x=2 and y=1) also produces good liquid suspensions in these formulations. A typical run, on a small scale of that procedure, can be described as follows:

Aluminum Ibuprofen 1:2 Salt

A stirred solution of sodium ibuprofen (22.8 g, 0.1 mole) in 200 ml of dionized water is heated to 65° C. and treated at the rate of 10 ml/min with a solution of aluminum chloride hexahydrate (10.84 g, 0.0449 mole) in 100 ml deionized water. The pH was monitored and held constant at 7.1-7.3 throughout most of the reaction by the addition of 43 ml of 1.0 N NaOH (0.043 mole). The temperature is allowed to drop to 50° C. and a white solid is collected by filtration. The solids are washed with water (6×100 ml) and the wet cake air dried. Final drying is done at room temperature for three hours over phosphorous pentoxide using high vacuum.

Analysis Calc'd for C ₂₆ H ₃₅ O ₅ Al: C, 68.70; H, 7.76; Al, 5.93; Found (corrected for water): C, 68.87; H, 7.69; Al (Ash), 6.24; Al (EDTA) 6.31; H ₂ O 0.77.

Optionally, the aluminum monohydroxy bis-ibuprofen salt obtained before drying can be washed with hydrochloric acid aqueous solutions, say, with sufficient 0.01 to 0.1 N hydrochloric acid to adjust the pH of the aluminum bis-ibuprofen salt/aqueous acid solution mixture to about 3 to 3.5 for about one hour to further purify the salt.

Aluminum monohydroxy bis-ibuprofen salts prepared in this manner have significantly higher surface area properties than aluminum ibuprofen salts prepared by prior art suggested methods such as the aluminum triethyl or aluminum isobutoxide diethyl methods set forth in Suzuki et al. U.S. Pat. No. 3,865,857 and German Offenlegungsschrift No. 2,213,704. Aluminum mono-hydroxy bis-ibuprofen salts can be prepared by this above herein-described Sinkula method having surface areas in excess of 7 square meters per gram, making the aluminum ibuprofen salts capable of delivering fully bioequivalent dosages in reasonably small drug vehicle amounts of ibuprofen equivalent as are obtained by present ibuprofen acid drug forms.

These new suspensions are designed and prepared so as to contain per a 5 ml dose between about 200 mg and about 600 mg of ibuprofen equivalent in the form of the aluminim ibuprofen salt. The weight percent of the aluminum ibuprofen salt is used which corresponds to the selected concentration. For example, for a pediatric suspension containing, say, about 200 mg of ibuprofen equivalent per 5 ml dose, the weight of an aluminum di-ibuprofen salt per 100 ml of suspension being prepared would be about 4.4 grams. For a normal adult size 400 mg dose of ibuprofen equivalent the weight content of the same aluminum di-ibuprofen salt would be about 8.8 grams and for a stronger 600 mg dose of ibuprofen equivalent, the dosage of such di-ibuprofen aluminum salt would be about 13.2 grams of this aluminum di-ibuprofen salt per 100 ml of suspension.

Because these are pharmaceutical suspensions, the grade of sucrose must be acceptable for pharmaceutical purposes, but tests at varying sucrose concentrations from 5 to 30 percent, w/v, indicate that variations in the dissolution rate of aluminum ibuprofen (A ₆₀ ) appears to be random and not correlatable to the sucrose content in the liquid suspension. The range of sucrose content in these liquid suspension compositions can be dictated by taste considerations. At least about 5 percent, w/v, of sucrose is needed for minimal sweetness and taste masking, if sucrose is to be the only sweetening agent in the composition, while sucrose contents above 25 percent, w/v, cause the suspensions to be too sweet. Viscosity and sedimentation properties of these liquid suspensions are not significantly affected over the 5 to 25 percent sucrose content range. At the preferred sucrose mid-range concentration (about 15 percent w/v) these liquid suspension formulations will provide about 0.75 gram of sucrose per 5 ml dose of the liquid suspensions.

Further, as the particle size of aluminum ibuprofen salt component in these liquid suspensions becomes finer and finer, say, sizes small enough to have surface areas approaching and preferably exceeding 7 square meters per gram, preferably, at this time, in the range of 12 to 16 square meters per gram, the viscosity of the suspension for an indicated amount of suspending agent in the suspension will tend to increase. This viscosity increase can be offset, if desired, by lowering the content of the suspending agent. For example, with our preferred finely divided aluminum bis-ibuprofen salt suspension compositions, the weight percent of the microcrystalline cellulose and sodium carboxymethylcellulose suspending agents amounts can be reduced to as much as one-half the amounts expressed in the Fitch/Rowe '440 Patent.

The suspending agents useful in the suspensions of this invention include Acacia U.S.P., Bentonite U.S.P., Carbomer N.F., Carboxymethylcellulose sodium U.S.P., Polyvinyl alcohol U.S.P., Povidone U.S.P., Tragacanth U.S.P., Xanthan Gum NF, Microcrystalline Cellulose N.F., and the like, which for the most part are powders having average particle sizes below about 50 microns.

Examples of preferred suspending agents for use in the pharmaceutical suspensions of this invention include:

(1) Avicel® RC-591, which is a commercially available microcrystalline cellulose marketed by FMC Corporation, Avicel Department, Marcus Hook, Pa., 19601, and which is said to be a colloidal form of about 89 percent miro-crystalline cellulose gel blended with about 11 percent sodium carboxymethyl-cellulose and dried, and which product is easily dispersed in water. It is insoluble in water, organic solvents and dilute acids. It is partially soluble in dilute alkali. Its physical and chemical specifications according to the national Formulary, Vol. XIV, are: Loss on Drying: not more than 8% of its weight; Heavy metals: less than 0.001% or 10 parts per million; viscosity of a 1.2 percent dispersion: 65±25 centipoise; pH of a 1.2 percent dispersion; 6 to 8; and assay:sodium carboxymethylcellulose content 11 (8.25 to 13.75) percent. Other similar pharmaceutical grade microcrystalline cellulose products can be used.

(2) Veegum® F is a microfine powdered magnesium aluminum silicate manufactured and sold by R. T. Vanderbilt Company, Inc., Specialties Department, 230 Park Avenue, New York, N.Y. 10017. This powdered suspending agent is said to be an inorganic, complex, colloidal magnesium aluminum silicate having an average chemical analyses, expressed as oxides as follows:

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Silicon dioxide 61.1 Percent Magnesium oxide 13.7 Percent Aluminum oxide 9.3 Percent Titanium oxide 0.1 Percent Ferric oxide 0.9 Percent Calcium oxide 2.7 Percent Sodium oxide 2.9 Percent Potassium oxide 0.3 Percent Carbon dioxide 1.8 Percent Water of combination 7.2 Percent

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which has a particle size which passes a 326 mesh screen.

We have found that for pharmaceutical liquid suspensions of aluminum ibuprofen meeting the above criteria, it is important to control the amount of suspending agent ranging from at least about 0.2 weight percent to about 1.1 percent by weight, preferably below about 2 percent, the particular amounts depending upon the choice of suspending agent. If the weight amounts of suspending agents are below the lower limits stated, the material does not suspend properly and, as a result, the solid components of the suspension precipitate to form a cake which is difficult to disperse; if the amounts of the suspending agents are much above the (1.1) weight percent range, the suspension becomes excessively thick and does not flow.

The wetting agents or surface active agents used in the suspension of this invention must be pharmaceutically acceptable, that is, non-toxic, and essentially water soluble in the amounts used and be effective to keep the solid form ingredients soluble or compatible with the suspension formulation. The wetting agent or surface active agent can be a non-ionic, anionic or cationic chemical compound or composition which should perform its function at a concentration of no more than about 0.8 weight percent, based on about 100 ml of liquid suspension. Examples of preferred water soluble wetting agents or surfactants for these aluminum ibuprofen suspensions include Polysorbate 80 (polyoxyethylene(20)sorbitan monooleate), Polysorbate 60 (polyoxyethylene(20)sorbitan monostearate), Myrj 52 (polyoxyethylenestearate U.S.P.), glycerol monostearate, glycerol monooleate, glycerol monoricinoleate, Pluronic F-68 (a polyoxyethylenepolyoxypropylene copolymer containing about 80 percent polyoxyethylene units and a polyoxypropylene moiety whose molecular weight is about 1750) as non-ionic surfactants, sodium lauryl sulfate as an anionic surfactant, and myristyl gamma-picolinium chloride as a cationic surfactant.

This invention is further illustrated, compared and exemplified by the following detailed preparations and examples, but they are not intended as limiting the scope of the invention.

PREPARATION I

Illustrative of Fitch/Rowe U.S. Pat. No. 4,145,440

Sorbitol/Glycerin Vehicle

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Ingredients Quantity

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Avicel RC-591® (a blend of 89% microcrystalline cellulose and 11% sodium carboxymethylcellulose NF low viscosity) 1.0% Carboxymethylcellulose Sodium USP Low viscosity 0.2% Glycerin USP 10.0% Sorbic Acid NF 0.2% Polysorbate 80 USP Food Grade 0.5% Sorbitol Solution 70% USP 20.0% Aluminum Ibuprofen 1:2 salt 8.8% 30% Solution Sodium Hydroxide (to adjust pH) Purified water USP q.s. ad 100.0%

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Directions

Disperse Avicel in .about.50% of the purified water while stirring at high speed for one-half hour. Wet the carboxymethylcellulose sodium with .about.one-third of the glycerin and add to the Avicel dispersion. While stirring constantly at a moderate speed, add the remainder of the glycerin, sorbic acid, polysorbate 80 and sorbitol solution. Mix well. Add the aluminum ibuprofen while stirring rapidly. Adjust to final volume with purified water. Adjust pH to 5.0, homogenize, and stir slowly to remove excess air.

Observations

Effect of Storage Conditions on Dissolution

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Age Temp. A 60 *

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Initial -- 100.1/100.5 1 week 47° 72.0/67.2 1 week 56° 38.1/38.1 1 week 70° 33.8/33.7 1 week 90° 22.4/23.3 4 mos. RT 67.8/70.8

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*A ₆₀ is the percent dissolved in one hour in pH 7.2 buffer at 37° C. A full description of the dissolution system is given below

Appearance

9 months ambient storage--slight sedimentation, resuspends easily.

This formulation has excellent properties: non-caking, resistance to gelling, good sedimentation, chemical stability and elegance. However, upon aging, the dissolution rate decreases drastically as indicated above. The present invention, as shown by the following examples, is a significant improvement over Example I.

Example I

Sucrose vehicle

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Ingredients Quantity

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Avicel RC-591® (a blend of 89% microcrystalline cellulose and 11% sodium carboxymethylcellulose) 1.0% Sorbic Acid NF 0.2% Polysorbate 80 USP Food Grade 0.5% Sucrose USP Granular 15.0% Aluminum Ibuprofen 1:2 Salt (5% excess) 9.63% Cherry-Vanilla flavor 0.032% Purified Water USP q.s. ad 100.0%

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Directions

Add the Avicel to .about.50% of purified water. Mix well for about thirty minutes while heating to 50° C. Add the polysorbate 80 and sorbic acid and mix until dispersed. Add the sucrose and flavoring and mix until dispersed. Add the aluminum ibuprofen and stir slowly until completely wetted. Pass suspension through a colloid mill, adjust pH to 5.0 and q.s. to final volume with purified water.

Observations

Effect of Storage Conditions on Dissolution

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Age Temp. A 60

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1 week 25° 10.54/107.6 1 week 56° 93.3/92.9 1 month 47° 97.8/100.6

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Appearance

4 months--slight sedimentation and gelling, suspension readily resuspends upon shaking.

This formula exhibits excellent sedimentation properties, elegance, etc. just as Preparation I does. However, it is superior to Preparation I in that the dissolution rate does not change significantly upon aging. The substitution of sucrose for sorbitol and glycerin has made the difference and it appears as if sorbitol and/or glycerin are responsible for the poor aging.

A series of experimental batches were made in order to determine the important factors in this aging phenomenon. The following four examples show that sorbitol and glycerin are the cause of decreasing dissolution rate.

PREPARATION II

Formula: No sorbitol

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Ingredients Quantity

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Avicel RC-591® (a blend of 89% microcrystalline cellulose and 11% sodium carboxymethylcellu- lose NF low viscosity) 1.0% Carboxymethylcellulose sodium USP Low Viscosity 0.2% Glycerin USP 10.0% Polysorbate 80 USP Food Grade 0.5% Sorbic Acid NF 0.1% Aluminum Ibuprofen 1:2 salt 8.8% 10% Solution Hydrochloric Acid (to adjust pH) Purified Water USP q.s. ad 100.0%

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Directions

Disperse Avicel in .about.50% of the purified water while stirring at high speed for .about.one-half hour. Wet the carboxymethylcellulose sodium with .about.one-third of the glycerin and add to the Avicel dispersion. While stirring constantly at a moderate speed, add the remainder of the glycerin, sorbic acid, and polysorbate 80. Mix well. Add the aluminum ibuprofen while stirring rapidly. Q.S. to final volume with purified water, adjust pH to 5.0, and homogenize.

Observations

Effect of Storage Conditions on Dissolution

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Age Temp. A 60

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Initial -- 94.3 1 week 56° 24.5

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Appearance

8 months--thick, smooth suspension, resuspends upon shaking.

PREPARATION III

Formula: No glycerin

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Ingredients Quantity

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Avicel RC-591® (a blend of 89% microcrystalline cellulose and 11% sodium carboxymethylcellu- lose NF low viscosity) 1.0% Carboxymethylcellulose Sodium USP Low Viscosity 0.2% Sorbic Acid NF 0.1% Polysorbate 80 USP Food Grade 0.5% Sorbitol Solution 70% USP 20.0% Aluminum Ibuprofen 1:2 salt 8.8% 10% Solution Hydrochloric Acid (to adjust pH) Purified Water USP q.s. ad 100.0%

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Directions

Disperse Avicel in .about.50% of the purified water while stirring at a high speed for .about.one-half hour. Add the carboxymethylcellulose sodium, sorbic acid, polysorbate 80 and sorbitol solution and mix well. Add the aluminum ibuprofen while stirring rapidly. Q.S. to final volume with purified water, adjust pH to 5.0 and homogenize.

Observations

Effect of Storage Conditions on Dissolution

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Age Temp. A 60

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Initial -- 102.8 1 week 56° 34.3

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Appearance

8 months--thick, smooth suspension, resuspends upon shaking.

EXAMPLE II

Formula: No sorbitol solution or glycerin

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Ingredients Quantity

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Avicel RC-591® (a blend of 89% microcrystalline cellulose and 11% sodium carboxymethylcellulose NF low viscosity) 1.0% Carboxymethylcellulose Sodium USP Low viscosity 0.2% Sorbic Acid NF 0.1% Polysorbate 80 USP Food Grade 0.5% Aluminum Ibuprofen 1:2 salt 8.8% 10% Solution Hydrochloric Acid (to adjust pH) Purified water USP q.s. ad 100.0%

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Directions

Disperse Avicel in .about.50% of the purified water stirring at a high speed for .about.one-half hour. Add the carboxymethylcellulose sodium, sorbic acid and polysorbate 80 and mix well. Add the aluminum ibuprofen while stirring rapidly. Q.S. to final volume with purified water, adjust pH to 5.0, and homogenize.

Observations

Effect of Storage Conditions on Dissolution

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Age Temp. A 60

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Initial -- 96.4/101.0 1 week 56° 100.2/97.5

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Appearance

8 months--sedimented slightly, resuspends easily.

EXAMPLE III

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Ingredients Quantity

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Aluminum Ibuprofen 1:2 salt 8.8% Polysorbate 80 USP Food Grade 0.5% Purified Water USP q.s. ad 100.0%

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Directions

Add the Polysorbate 80 to .about.50% of the purified water and mix well. Add the aluminum ibuprofen while stirring rapidly. Stir for .about.three days, q.s. to volume with purified water and homogenize at tight setting.

Observations

Effect of Storage Conditions on Dissolution

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Suspension Age Temp. A 60

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A 1 week RT* 93.8 B 1 week 56° 93.1

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RT* = Room Temperature

Appearance

Suspension readily sediments and has a tendency to cake.

The above preparations and examples clearly show that both sorbitol and glycerin cause aluminum ibuprofen to become less reactive, i.e., hydrolyze and dissolve more slowly. This was unexpected since prior experimental work on an analogous compound showed that sorbitol and other polyhydroxy compounds actually inhibited the decreasing reactivity of Al(OH) ₃ that normally occurs on aging. See S. L. Neil et al., J. Pharmaceutical Sciences, 65, 1195 (1976). The effect can be explained by hydrogen bonding between the hydroxyl groups of sorbitol and the edge of the hydroxy aluminum particles which inhibits the secondary polymerization reaction. It was surprising, then, that sorbitol would actually catalyze the aging effect of these aluminum salts. In addition, it was totally unexpected that sucrose would behave so differently from other sweetening agents.

Dissolution Test Method

A dissolution test method for the purpose of obtaining comparable dissolution rate numbers for various aluminum ibuprofen liquid suspensions is given below:

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Dissolution Conditions

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Apparatus: RFSB dissolution system* Sample size: 2.0 ml aluminum ibuprofen suspension (80 mg/ml) Dissolution Fluid: 900 ml 0.05M KH 2 PO 4 pH 7.2 buffer Temperature: 37° C. Agitation Speed: 600 rpm Filter: 1/2 μm glass filter

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*Rotating filter stationary basket system. U.S. Pat. No. 3,801,280, ACShah and CBPeot (to The Upjohn Co.), April 2, 1974

Procedure for Dissolution Studies

The equivalent weight of 2.0 ml of suspension (based on the specific gravity of the suspension) is added at time zero to each beaker containing 900 ml of pH 7.2 buffer. The containers are rinsed and the washing added to the dissolution beakers. 10.0 ml of filtrate are withdrawn manually at specified times and placed in 20 ml scintillation vials. Intermittent pumping is used prior to sampling to obtain a uniform sample of filtrate. An empty basket is inserted to eliminate any vortex. All samples are immediately refiltered through a 0.45 μm millipore filter. 1 N NaOH solution is added to each beaker after sampling to adjust pH of phosphate buffer to ca 11.0. A final sample is withdrawn after twenty-four hours in order to assay for total amount of ibuprofen present. This concentration is used as D ₁₀₀ %, the theoretical amount ibuprofen present.

High Pressure Liquid Chromatography Conditions

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Column: EM Hibar II Lichrosorb RP-8, 10 μm, or equivalent Reverse phase column Solvent: Acetonitrile-pH 7.2 phosphate buffer 40:60; pH adjusted to 7.3. Internal Standard: 0.002M acetophenone in pH 7.2 phosphate buffer Flow Rate: 1.5 ml/min Pressure: 1000-1500 psi Pump: Altex 110A Solvent Metering Pump, or equivalent Detector: Hitachi 100-40 UV-VIS variable wavelength spectrophotometer, or equivalent Wavelength: 230 nm Slit Width: 2.0 nm Scale Setting: 0.3 ABS Attenuation: 128 Integrator: HP 3380A integrator-recorder, or equiva- lent Sampler: WISP 710 automatic sampler, or equivalent Sample size 50 μl injected:

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Alternate High Pressure Liquid Chromatography Assay Conditions

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Column: Microbondapak C 18 reversed phase (Waters) or equivalent Pump: Dual head LDC (Milton Roy Minipump), or equivalent Detector: UV using a Beckman DUR Spectrophotometer, or equivalent Injector: Rheodyne loop (20 μl) injector, or equivalent Scale setting: 0-0.56 AUFS Solvent: UV acetonitrile-water-acetic acid (50:50:0.5) Sample: 20 μl containing 0.05-0.5 mg/ml Flow rate: 2.5 ml/min Wavelength: 228 nm

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External Standard Preparation

External standard is prepared by dissolving a known amount of ibuprofen in 7.2 phosphate buffer. Repetitive injections are made and an average amount/area ratio of internal standard and ibuprofen standard is used in programming the integrator.

Sample Preparation

Equal volumes of sample filtrate and internal standard solution are mixed and then an aliquot of this mixture is injected on the column.

Calculation of Percent Ibuprofen Dissolved

The Internal standard method using the HP 3380 integrator is used in calculating concentration of ibuprofen in samples.

Example: Theoretical amount (D ₁₀₀ %) of ibuprofen present in 2.0 ml of suspension=160 mg. ##EQU1##

EXAMPLE IV

Comparison of effect on aluminum ibuprofen dissolution rates (A ₁₀ ) by various saccharides and sweeting agents.

A number of sweetening agents which are commonly used in liquid pharmaceutical formulations for oral use were incorporated into a standard formulation, set forth below, and then tested by means of a dissolution rate test.

The test formulation was as follows:

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Ingredients Quantity per 100 ml

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Microcrystalline cellulose and carboxymethylcellulose sodium N.F., low viscosity 0.5 gm Polysorbate ®80 N.F. 0.5 gm Sorbic Acid N.F. 0.2 gm Cherry vanilla flavor 0.005 ml Aluminum ibuprofen, as in 8.8 gm Preparation 1, above 10% solution hydrochloric -- acid to adjust pH to 5.0 Test sweetening Agent 10 gm (Sucrose) Purified water, q.s., ad 100 ml

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In these tests, 10 grams of each sweetener was used, regardless of its relative sweetness, to determine the respective affects of the test sweetener on the dissolution rate of the aluminum ibuprofen active ingredient in the respective formulations. It is understood that when the desired sweetener is selected, the weight amount thereof will be adjusted within the above indicated ranges in the total formulation to obtain as closely as possible a desired degree of sweetness in the formulations.

The respective test liquid pharmaceutical suspensions were tested within a few days after preparation (initial A ₁₀ values) and then tested again after storage of a portion of the same pharmaceutical liquid suspension for one week at 56° C. (one week 56° C. A ₁₀ value). This accelerated aging simulates (in the laboratory) longer term aging at 25° C. in warehouse storage.

The dissolution rate test is run as follows:

Two ml of the test suspension are added at time zero to 900 ml of pH 7.2 phosphate at 37° C. The liquid mixture is stirred continuously at 600 rpm. by means of a rotating filter apparatus. Samples of the stirred mixture are taken periodically, filtered and assayed for dissolved ibuprofen (free acid) content by high pressure liquid chromatography. Examples of typical dissolution curves for glycerin and sucrose test sweeteners are attached hereto as FIGS. 1 and 2, respectively.

The percent ibuprofen (free acid) dissolved in 10 minutes (A ₁₀ ) is an effective dissolution parameter for comparing the effect of the test sweetener (or blank) on the dissolution rate of the aluminum ibuprofen in the respective test suspension.

The suspensions dissolve more slowly as they age, even the very simplest suspensions containing only aluminum ibuprofen and the surfactant. The following commonly used pharmaceutical excipients (for sweetening) cause a substantially more serious aging effect as measured by the A ₁₀ value after one week of storage in the accelerated aging test at 56° C.

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A 10 , % Test Sweetening Agent Initial After 1 week/56° C.

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Glycerin 80.5 12.6 Sorbitol/Glycerin (50/50 w/v) 93.7 9.2 Xylitol 86.8 23.9 Manniol 90.9 48.0 Arabitol 89.8 46.6

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The following group of compounds are uniquely different from the above sweetening agents in that they are pharmaceutically acceptable sweeteners which do not cause substantial reduction of the dissolution rate with the test period of time.

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A 10 , % Test Sweetening Agent Initial After 1 week/56° C.

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None 85.1 69.2 Sucrose 92.8 59.8 Fructose 89.5 60.4 Glucose 90.7 59.3 Sodium Saccharin 90.0 63.4

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In the drawings, FIG. 1 shows graphically the relationship between the percent ibuprofen dissolved (ordinate) over time periods of up to 1 hour (abcissa) from alumina ibuprofen pharmaceutical suspensions prepared as above combining 10 percent w/v of glycerin as the sweetening agent initially (top line) and after one week of 56° C. aging of the suspension. The FIG. 1 graph shows that the A ₁₀ value for the initial sample is about 80.5% dissolved and the A ₁₀ value for the one week accelerated aged sample is about 12.5% dissolved.

In FIG. 2, in a similar graph of the relationship between the percent ibuprofen dissolved initially, and after 1 week of 56° C. aging of aluminum ibuprofen pharmaceutical suspensions using vertical suspensions using 10 percent w/v of sucrose as the sweetening agent, the graph shows that the reduction of ibuprofen dissolution rate is not nearly as great using sucrose as the sweetener. The FIG. 2 graph shows that the initial A ₁₀ value for the sucrose containing pharmaceutical formulation is about 92.5 percent and that the one week 56° C. aging A ₁₀ value of the same sucrose formulation is about 60 percent.